PROJECT SUMMARY/ABSTRACT Overview: The goal of this award is to provide Dr. Deborah Stephens, with training and mentored research experiences that will facilitate her transition into the role of an independent investigator in experimental therapeutics and mechanisms of resistance to cancer therapies for patients with lymphoid malignancies. Her long-term career goal is to become a clinical/translational investigator who contributes new knowledge to the field, impacts how we think about lymphoma, and helps to improve patient outcomes. Research: Relapsed/refractory chronic lymphocytic leukemia (CLL) and non-Hodgkin?s lymphomas (NHLs), are common, incurable malignancies that contribute significantly to cancer mortality. Recently, novel targeted therapies have improved clinical outcomes. However, patients who develop therapy resistance have very poor outcomes. The proposed research aims to understand, prevent, and overcome this therapy resistance. This proposal includes two clinical trials that involve rational combination therapies with the aim to mechanistically prevent treatment resistance. Longitudinal samples from patients treated on the proposed clinical trials will be analyzed by targeted and whole exome sequencing. A novel computational tool developed at the University of Utah will be used to study the evolution of sub-clonal cancer cell populations. The proposed trials introduce two novel and rational combination therapies that could change the current paradigm of CLL/NHL therapy. Correlative studies will provide new insights into the mechanisms governing response and resistance to BCR inhibitor combinations, and identify biomarkers for early identification of patients at risk of relapse. The combination of rationally designed early clinical trials with molecular studies to identify the causes of response and resistance will provide Dr. Stephens with the training needed to become a successful clinical translational researcher in lymphoid malignancies and provide the basis for R-level funding to gain academic independence. Career Development Plan/Environment: Dr. Stephens is an oncologist with a strong foundation in translational research in the field of lymphoid malignancies. The K23 graduate coursework, targeted training, seminar attendance, and mentored research experiences will provide the skills and experiences Dr. Stephens needs to become an independent investigator in lymphoid malignancies. During this award, Dr. Stephens will acquire new content area knowledge in genomic and bioinformatics analysis. She will gain practical skills in clinical trial design, management, genomic analysis, and working collaboratively with an extensive multi-disciplinary research team. Dr. Stephens has assembled a highly experienced and internationally-recognized mentoring team, who will provide guidance in translational cancer research. The Huntsman Cancer Institute, an NCI- designated Comprehensive Cancer Center and the University of Utah provide a rich environment for the development of junior faculty and unparalleled opportunities for multidisciplinary cancer research collaborations.